The increasing incidence of obesity is a major health issue facing the USA. Fortunately, in the past decade several key hormones and CMS pathways controlling body weight and glucose homeostasis have been identified. Indeed, we now have a rough CMS roadmap through which key metabolic signals such as leptin exert its effects. If effective strategies to combat the incidence of obesity and eating disorders are to be developed, an increased understanding of the molecular mechanisms underlying coordinate energy homeostasis is required. Recently, we have assembled a team of investigators whose goal is to delineate the neural substrates underlying coordinated control of food intake, body weight and glucose homeostasis. In the current application, we provide a series of studies designed to increase our understanding of the hypothalamic control of liver metabolism. We will also investigate mechanisms by which the hypothalamus regulates complex feeding behavior, especially the rewarding nature of high fat diets. First, we will investigate mechanisms by which leptin and serotonin acting on hypothalamic POMC neurons regulate hepatic glucose and lipid metabolism. Second, we will investigate the interaction of hypothalamic pathways controlling body weight with the brain pathways regulating complex appetitive behavior and reward. We hypothesize that these reciprocal connections are crucial for regulating responses to natural rewards including high fat diet. Finally, in parallel to our mouse studies in Aims 1-2, we will, in postmortem human brain tissue, quantitatively assess alterations in genes whose expression we hypothesize is altered in obese humans and those with drug-induced metabolic syndrome. The timely translation of hypotheses based on animal models to the human is one of the primary goals of the Taskforce on Obesity at UT Southwestern Medical Center at Dallas, and we are uniquely poised to make major strides in translational research of obesity.